Obesity has become one of the most pressing public health issues of the current century. Unfortunately, tackling the high incidence of obesity is proving to be extremely difficult. The initial discovery of leptin, an adipocyte-derived hormone that acts on hypothalamic neurons to suppress appetite and regulate energy expenditure, raised hope for an obesity therapy. However, its therapeutic use is hampered by the development of leptin resistance in obese humans, a phenomenon for which the precise molecular mechanisms are not fully understood. Interestingly, endoplasmic reticulum (ER) stress is associated with obesity and implicated in leptin and insulin resistance in peripheral tissues and in the brain. Recent evidence suggests that a key site involved this stress response is the hypothalamus. Arcuate POMC neurons are key targets of leptin and insulin action, and normal melanocortin signaling is required for normal food intake, body weight, and euglycemia. Thus we hypothesize arcuate POMC neurons are involved in this hypothalamic stress response. The proposed experiments make use of mouse models unique to the Elmquist laboratory and our collaborators to investigate the role of metabolic and cellular stress in the development of central leptin and insulin resistance. In Aim 1A, we will extend our preliminary observations and examine the effects of free fatty acids and other chemical stimulators on leptin and insulin signaling in POMC neurons. In aim 1B, mice which selectively overexpress XBP1s in POMC neurons (POMC-XBP1s) will be used to investigate the role of the unfolded protein response in leptin and insulin signaling following stimulation by these metabolic and cellular stressors. In Aim 2, POMC-XBP1s mice will be used to determine if enhanced XBP1s signaling can defend against diet-induced obesity and accompanying co-morbidities. In summary, the proposed studies will comprehensively test the action of metabolic and cellular stress in POMC neurons and their subsequent effect on the development of obesity and central leptin and insulin resistance. PUBLIC HEALTH RELEVANCE: The proposed studies will greatly increase our understanding of the mechanisms underlying leptin and insulin resistance and obesity. The study findings will provide valuble information with which to develop treatment strategies for the prevention of obesity and diabetes.